Enteric-coated pilules



United States Patent O 3,081,233 ENTERIC-COATED PILULES Walter F. Enz,Kalamazoo Township, Kalamazoo County, and Thurlow E. King, PavilionTownship, Kalamazoo County, Mich., assignors to The Upjohn Company,Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Aug. 8,1960, Ser. No. 47,951 17 Claims. (Cl. 167-82) This invention relates tonew dosage forms for medicinals, and more particularly relates topharmaceutical preparations containing enteric pilules measuring notmore than about Oil inch in diameter, the coating being a single,non-toxic, acidic, enteric film-forming material.

Many medicinals are most satisiactorily administered in an entericdosage form. However, many difliculties have arisen in the attempt toproduce an enteric dosage form which ideally performs its function. Manyenteric dosage forms will partially disintegrate in the stomach. Someenteric dosage forms have been known to pass completely through thegastrointestinal tract without disintegrating at all. Such entericmedicinals are erratic and unreliable. This difliculty is magnified inthe case of medicinals taken at or near mealtime. The slower passage ofthe medicinal through th stomach when taken during this period generallyhas an adverse effect upon its absorption into the human system.Moreover, any enteric dosage form, since it does not disintegrate untilreaching the intestine, necessarily involves a delay before themedicinal ingredient begins to take effect.

It is therefore :an object of the present invention to provide a newenteric dosage form which is well adapted to oral therapeutic use.Another object is to provide such a dosage form which is innocuous tothe taste and is especially well-adapted to pediatric use. Another'object is to provide such dosage forms which :are not disintegrated inthe stomach, and yet are readily available for absorption in the upperintestinal tract. Still another object is to provide such a dosage formwhich gives better therapeutic results. Still another object is toprovide such a dosage form for medicinals absorbed into the blood whichgives appreciably faster, higher and/or more consistent bloodlevels thandosage forms available to the prior art. "Still another object is theprovision of a novel process for the preparation of such a dosage form.Other objects will be apparent to those skilled in the art to which thisinvention pertains.

The foregoing and additional objects have been accomplished by theprovision of an oral pharmaceutical preparation containing uniform,spherical, enteric pilules measuring not more than about 0.1 inch indiameter comprising '(a) a medicinal agent and (b) :a coating of asingle enteric film-forming material. The pilutes will not disintegratein the mouth and can be sugar coated so that taste of the medicinal iscompletely masked. Moreover, the medicinal in this form will not berapidly destroyed in the stomach, will not cause nausea or otherirritation, and can be given irrespective of meals. It is particularlywell adapted to pediatric use since children may take it .at anysuitable time. No efiort need be made to predetermine a childs diet forthe sake of administering the medicinal whereas most products previouslyavailable, erythromycin, for example, had to be given on a tastingstomach for maximum results. Since pilules can be mixed with food, thetendency of small children to 3,081,233 Patented Mar. 12, 1963 iceresist the administration of medicine is minimized. These pilules areeffective enough to be given irrespective of mealtime and also areappreciably better therapeutically. In the case of medicinals absorbedinto the blood, higher and more consistent blood levels, as well as moreprolonged blood levels, are obtained with these pilules than withsimilarly coated larger dosage forms. The reason for this is unknown.Several reasons have been hypothesized but none has yet beensubstantiated. However, it is clear that superior therapeutic resultsare obtained with the dosage form of the present invention.

The enteric pilules can be formulated into a variety of finishedpharmaceutical forms, for example, packets, twopiece hard gelatincapsules which can be sealed, one-piece sofit gelatin capsules, liquidsuspensions, and the like.

In one embodiment of the invention the pilules are prepared by rollingthe desired medicinal on moistened pill starters until small pills(pilules) are produced. The pilules are dried and subsequently coatedwith the enteric coating material.

A large number of medicinal agents can be prepared in the dosage formsof the present invention. Although the reasons for enteric coating thesematerials are different, the advantages inherent in the dosage form ofthe present invention are the same for each of these materials, i.e.,quicker, better land/or more consistent therapeutic results are obtainedin the dosage form of the present invention. For medicinals, such aserythromycin and penicillin, which are absorbed into the blood streamthese advantages show up as quicker, higher and/or more consistent bloodlevels. These advantages together with advantages in actual use, such asadaptability to pediatric use, case of ingestion, innocuousness, andadministration irrespective of mealtime, result in an ideal dosage formfor a large number of medicinal materials, including the following (thereasons given are specific and in addition to the foregoing):

(a) Sedativesphenobarbital, sodium pentobarbital,cyclopentenylallylbarbituric acid, etc, to overcome bitter taste.

(b) Antipyreticsaspirin, salicylamide, sodium salicylate, etc, toovercome bitter taste, reduce gastric irri-. tation, and improvestability.

(0) Antibiotics-erythromycin, tetracycline, penicillin and the like, toavoid destruction in the stomach and improve taste.

(d) Antispasmodiosatropine, methscopolamine bromide, methscopolaminebromide with phenobarbital, to improve taste.

(e) Nutritional agents-multiple vitamins to improve taste and stability.

(f) Hematinics-ferrous sulfate, B intrinsic factor, etc, to reducegastric irritation, eliminate discoloration of teeth and improve taste.

(g) Laxative-prune powder, to improve taste.

(h) Anthelmintics-santonin, piperazine citrate, etc., to improve taste,reduce irritation in mouth and stomach.

(i) Expectorant-arnmonium chloride, to improve taste and reduce gastricirritation.

(j) Hormones-adrenocorticosteroids, for example, 6a-methylprednisolone,hydrocortisone, and 9a-fiuoro- 16a-hydroxyprednisolone; androgenicsteroids, for example, methyltestosterone, and9a-fluoro-llp,l7fi-dihydroxy-17a-methyl-4-androstene-3-one; estrogenicsteroids,

for example, l7fi-estradiol and 17-ethinyl, 3,17-cstradiol; andprogestational steroids, for example, 17a-hydroxyprogesterone acetate,6ct-methyl-17a-hydroxyprogesterone 17-acetate, andl7a-ethinyl-19-nortestosterone; to attain prolonged blood levels.

(k) Psycic energizer agents, for example, indole, 3-(2-aminopropyl)-,acetate and indole, 3-(2-aminobutyl)-, acetate, to attain prolongedabsorption.

(1) Antimony potassium tartrate, to attain prolonged absorption.

Many non-toxic acidic enteric materials are suitable for the noveldosage forms of the present invention. In general such enteric materialsserve the purpose of resisting disintegration of the coating until thepilules pass through the stomach into the intestine. Illustrativeenteric materials and mixtures containing such materials includekeratin, formalized gelatin, calcium alginate, shellac and likenaturally occurring resinous substances, cellulose acetate phthalate,starch acetate phthalate, amylose acetate phthalate, partiallyhydrolyzed styrene-maleic anhydride copolymer, styrene-maleic acidcopolymer, polyvinyl acetate phthalate, and polyvinyl hydrogenphthalate;shellacwool fat, shellac-caster oil, shellac-cetyl alcohol,shellacammonia, shellac-ammonia-alcohol; and the like.

The size of the finished pilules is very important. The size of the pillstarters depends upon the finished size of the pilules to be producedand the amount of the other ingredients to be used therein. The amountof active material and the thickness of the enteric coat is adjusted toobtain a pilule not exceeding about 0.1 inch in diameter. It ispreferred that the finished pilule range in size between about 0.04 andabout 0.085 inch in diameter. The finished pilule size is a criticalfeature of the present invention.

In a more specific embodiment of the present invention an unweighedquantity of bolted sucrose (30 40 mesh) is placed in a revolving pilltub and moistened with a spray of deionized or distilled water untiluniformly moistened. Uniformity in size of the bolted sucrose is moreimportant at this stage than is the relative size of the sucrosegranules. A small amount of a homogeneous mixture of talc, starch andsucrose (20:5:1) is dusted on the moistened sucrose. The tale, starch,sucrose mixture rolls onto the moistened sucrose. The contents of thepill tub are alternately water-sprayed and powder-dusted until sphericalmasses, called pill starters, are produced. The smaller spheres, whichare separated from the larger spheres by screening during processing,are returned to the pill tub and brought up to proper size by the abovedescribed method. Those spheres which are out of shape at this point arepreferably discarded. Only round, smooth starters are desirable.

A sufficient number of the spheres (or pill starters) of the proper sizeare placed in a revolving pill tub and sprayed with distilled ordeionized Water until the pilules are uniformly moistened. A homogeneousmixture of the desired medicinal (e.g., erythromycin) three parts, talc7.5 parts, starch two parts and sucrose one part, is dusted on themoistened pill starters. Again the water spraying and powder dusting arerepeated alternately until the pilules are of the proper size. Thepilules are air dried and then assayed for content of the activematerial.

Afterthe pilules have dried and the content of medicinal has beendetermined, the pilules are given several coats of an enteric material,using tale for dusting. Thus the finished pilules are built up from aninert core by adding 1) a layer containing a medicinal agent, and (2) anouter layer containing a single, non-toxic, acidic, enteric film-formingmaterial.

In all cases approximately nine-tenths of the finished enteric coatedpilules must resist artificial gastric juice (pH 1.2) for at least sixtyminutes. The coatings designed to make the medicament rapidly availableshould disintegrate within sixty minutes in pH 6.8 buffer solution(citrate phosphate buffer) at 37 degrees Centigrade when subject tocontrolled and constant agitation in the buffer solutions. The coatingsdesigned to provide prolonged availability of the medicament shoulddisintegrate over a period of from about one to about seven hours inbuffers from pH about 3.0 to about 8.0.

The enteric coated pilules can be sugar coated if desired and are nowready for therapeutic use. They may be mixed with various foods andtheir size is such that the average person taking the'pilules will beunaware of their presence in the food. Therapeutic doses are generallyprepared in packets and capsules to better control the amount of eachdose. Pilules containing one active material may also be mixed withother pilules containing other active materials for combined treatmentwith two or more active materials.

While it is not believed to be absolutely essential that the dosage formof the present invention be limited to spherical pilules from thestandpoint of therapeutic results, it is desirable for other reasons.Appearance is better when the individual units are uniform. The dosageof active ingredient is easier to control when the units are uniform.The thickness of the enteric coat and the uniformity of the enteric coatare more difficult to control for irregularly shaped solids. Moreover,the size of the units is easier to control if prepared in a uniformmanner, and spherical units are easier to administer and lessirritating.

The following examples are illustrative of the process and product ofthis invention and are not to be construed as limiting.

EXAMPLE 1 Erythromycin Pilules of the pill tub are alternately watersprayed and powder dusted until spherical masses, called pill starters,having a diameter between 0.040 and 0.050 inch, are produced. Thesmaller spheres are separated from the larger ones by screening duringprocessing. They are returned to the pill tub and brought up to theproper size by the above described method. Those spheres which are outof shape at this point are discarded. Only round, smooth starters areused to form pilules.

To prepare 50,000,000 pilules the following types and amounts ofingredients would be required:

Pill starters 50,000,000. Erythromycin crystalline base 59 lbs. 4 oz.Talc, bolted 224 lbs. Starch, bolted 64 lbs. Cane sugar powder, U.S.P 32lbs. Color 1 lb.

The pill starters are placed in a revolving pill tub and sprayed withdeionized water until the pilules are uniformly moistened. A homogeneousmixture of erythromycin three parts, talc 7.5 parts, starch two partsand sucrose one part, is dusted on the moistened pill starters. Thewater spraying and powder dusting are repeated until the pilules rangein size from 0.065 to 0.071 inch in diameter. The pilules are air driedand assayed for erythromycin content.

After assay, the pilules are given several coats of cellulose acetatephthalate described in U.S. Patent 2,196,768 in an absolutealcohol-acetone solution having one to one ratio using tale for dusting.This procedure is continued until round and smooth pilules ranging insize from 0.065 to 0.085 inch in diameter are obtained.

The coating of the pilule should resist artificial gastric juice (pH1.2) for at least sixty minutes and should disintegrate within sixtyminutes in pH 6.8 butler solution (citnate phosphate buffer) at 37degrees centigrade when subjected to controlled and constant agitationin the butler solutions.

The pilules are packaged in groups of 100, each packet supplying onetherapeutic dose of about fifty milligrams (allowing for losses inmanufacture and storage).

EXAMPLE 2 Salicylate Pilules Following the procedure of Example 1pilules containing sodium salicylate as the active ingredient and coatedwith ammoniated shellac can also be prepared by substituting sodiumsalicylate for erythromycin and ammoniated shellac for cellulose acetatephthalate.

For 1,000,000 such pilules the following types and amounts ofingredients would be required:

Sodium salicylate, 3 lbs. 9 oz. 63 grs. Talc, 3 lbs. 5 oz. 313 grs.

Starch, 1 lb.

Cane sugar, 8 oz.

The superior therapeutic results obtained by the dosage form thusproduced are illustrated by Table VI.

EXAMPLE 3 Ferrous Gluconate Pilules One million pilules containingferrous gluconate as the ingredient are prepared from the followingtypes and amounts of materials.

FERROUS GLUCONATE PILULES, 1,000,000

Ferrous gluconate, N.F., 3 lbs. 9 oz. 63 grs. Talc, U.S.P., 4 lbs. 8 oz.

Bolted starch, 1 lb. 4 oz. 250 grs.

Cane sugar powder, U.S.P., 10 oz. 125 grs.

Round, smooth pill starters are prepared as described in Example 1. Onemillion of these pill starters are placed in a revolving pill tub andsprayed with deionized water until the pilules are uniformly moistened.A homogeneous mixture of ferrous gluconate 6.25 parts, talc seven parts,starch two parts and cane sugar one pant, is dusted on the moistenedpill starters. The Water spraying and powder dusting are repeated untilthe pilules range in size from 0.065 to 0.075 inch in diameter. Thepilules are air dried and assayed for ferrous gluconate content.

After assay, the pilules are replaced in a pill tub and given threecoats of a thirty percent shellac in ethanol solution using talc fordusting. The pilules are then dried with a blast of hot air and twocoats of a solution of gelatin, sucrose and water are applied with talcfor dusting. A sufiicient number of coats of the gelatin-sucrosesolution are applied using a mixture of precipitated calcium carbonate,talc and acacia, for dusting until 100 pilules laid end to end measurethree and one-half inches. Then sufficient number of coats of a syrupsolution with the car-bonate-talc-acacia mixture as a dusting powder areapplied until the pilules are perfectly round. A syrup solutioncontaining coloring material is applied to give the proper finishedcolor to the pilules.

Those pilules having a diameter less than .065 inch or greater than .085inch were discarded. One hundred pilules gave a therapeutic dose of 2.5grains of ferrous gluconate.

EXAMPLE 4 Penicillin Pilules inch in diameter were discarded. By assaypilules thus produced contained 1286 units of penicillin per pilule.

I 6 Eighty such pilules provided a therapeutic dose of about 100,000units of penicillin.

EXAMPLE 5 Tetracycline Hydrochloride Pilules ANIMAL DATA The followingdosage forms were compared for blood levels in dogs:

-I. Tablet A--enteric coated erythromycin (commercially availableproduct) Tablet 'B--non-enteric erythromycin Suspension-erythromycin asthe ethyl carbonate in an orally acceptable vehicle (commerciallyavailable product) Pilules-enteric coated erythromycin II. III.

Eleven mongrel male dogs were used for this investigation. They aredesignated by number as 201, 202, 203, 204, 205, 210, 216, 218, 220,222, and 224. In each experiment the dogs were starved eighteen hoursprior to administration of the drugs. Except where otherwise indicatedin the tables, each dog was given approximately 25 milligrams oferythromycin per kilogram of body weight orally and immediatelythereafter fed a full can of dog food. The animals were then permittedto eat a regular laboratory diet ad lib throughout the day. Except whereotherwise indicated, blood samples were taken shortly before theadministration of the drug and usually every hour thereafter for aperiod of eight hours. Some dogs were run more than once on difierentdays with the same or different dosage forms. Serum samples were assayedfor erythromycin by a modification of the Rammelkamp (serial dilution)method employing Streptococcus hemolyticus as the test organism. Theresults are presented in the following tables (I through VI) and aregiven in terms of micrograms of erythromycin per milliliter of serum.Essentially, the tables are arranged and numbered in the same order asthe dosage terms listed immediate, higher and more consistent bloodlevels.

TABLE I.TABLET A (ENTERIC COATED) Time (hours) 201 201 202 202 203 TABLEII.'IABLET B (UNCOATED) Time (hours) 201 202 203 Tables I, II, and IIIshow that the maximum blood level which can be reasonably expected fromthe usual dosage forms is about one microgram of erythromycin permilliliter of serum and that the maximum is not obtained until thefourth hour or later.

TABLE IV.ENTERIC COATED PILULES Hour Dog 204 Dog 205 Dog 210 Dog 220 Dog222 Although Table TV shows that the enteric coated pilules of thepresent invention are superior in many respects to the other dosageforms, the most striking difference is the fact that after one hour theenteric coated pilules give four times as high a blood level as theenteric coated tablets.

A similar experiment has been conducted with penicillin as the activeingredient in the dosage form prepared in the manner described inExample 4. Regular sized gelatin capsules were compared with uncoatedpilules and enteric coated pilules. Again the dosage form of the presentinvention proved to be superior to the other forms in providing moreimmediate, higher and more consistent blood levels. The data aresummarized in Table V.

TABLE V.SERUM LEVELS OF PENICILLIN IN DOGS FOL- LOWING ORALADMINISTRATION OF GELATIN CAP- SULES, COATED AND UNCOATED PILULES Dog204 Dog 222 Hours Gelatin Uncoated Enterlc Gelatin Uncoated Entericcapsules pilules coated capsules pilules coated pilules pilules Thesedata show at least a two fold increase in blood levels for the entericpilules of the invention.

Still another experiment was conducted with the pilules containingsodium salicylate and described in Example 2. The plasma levels ofsalicylic acid in blood from starved adult female dogs were determinedby oral administration of fifty milliliters of 0.1 normal hydrochloricacid followed by either the ammoniated shellac coated tablets orammoniated shellac coated pilules given in a single No. 11 gelatincapulse (veterinary /2 oz. capsule, Eli Lilly and Company).

The sodium salicylate was administered at the level of 113 mg./ kg. ofbody weight. Four five grain tablets contained about 1300 milligrams ofsodium salicylate while some 700 odd pilules were used to give 1300milligrams of the drug. These two drug preparations gave similardisintegration times in vitro. The data obtained, summarized in TableVI, gives striking evidence of quicker,

form of TABLE VI 7 Salicylic acid/ml. plasma Do Dose type 1 hr. 2 hrs. 3hrs. 5 hrs. 7 hrs.

A Tablets..- 0 5 5 147 154 Pilules 122 134 146 155 B Tablets 4 8 22 27Pilules. 102 172 177 172 163 C Tablets 0 4 4 22 38 Pilules. 78 126 155137 134 D Tablets. 0 0 0 11 35 Pilules. 67 137 179 193 186 [Averageranges for tablet vs. pilules in dogs] Average 7 salicylic acid/ml.plasma Dose 1 hr. 2 hrs. 3 hrs. 5 hrs. 7 hrs.

Tablets l 2 8 52 81 (0-4) (0-8) (0-22) (11-147) (35-154) Pilules 83 161162 159 HUMAN USE The experiments given above in animals have beenduplicated in humans, and the results have reaflirmed the conclusionsthat enteric coated pilules give higher, more immediate, and/ or moreconsistent blood levels than other dosage forms containing the sameactive material.

In general it should be noted that with all enteric coated dosage forms,there is a delay in the onset of maximum average blood levels ascompared with nonenteric forms when the dosage form is administered withor immediately after meals. This is due to the additional time requiredfor emptying the stomach following a meal providing an opportunity forthe enteric coat to disintegrate in the upper intestine. When suchdosage forms are administered on an empty stomach, peak blood levels areattained much more rapidly. In either case, however, the smaller pilulesof the present invention give more efficient utilization of activematerial in providing higher, more consistent and more immediate bloodlevels than either larger dosage forms or suspensions.

Since the dosage form of the present invention is believed to beespecially adaptable to pediatric use, it was tested on a group ofeighteen children ranging in age from four months to fourteen years totest for patient acceptance. Among the various foods used as vehicleswere pureed peaches, carrots, pears, pablum, apple sauce, beef,potatoes, rice, green beans, tomatoes, ice cream, soup, chocolatepudding, juice, and cereal. In general, acceptance was good, and thestudies show that the pilules should be mixed with food that does notrequire mastication, such as pureed fruits, pudding, juice and the like.

The enteric coated erythromycin pilules were used to treat five childrenunder two years of age at a dose of five milligrams per pound. Thepilules were administered on a dry spoon or mixed with pudding and weretaken without objection by the children. The following Table VIIsummarizes the blood levels obtained in micrograms of erythromycin permilliliter of blood.

Tables VIII and IX illustrate the superiority of the pilules over acomparable suspension when administered to children.

TABLE VIII.ERYTHROMYCIN PILULES [Single dose, 5 mg./lb.]

Blood levels, meg./m1. Age Weight Dose,

in lbs. mg.

1 hr. 2 hrs. 3 hrs. 4 hrs. 5 hrs. 8 hrs.

Average 24 4. 4 1.7 2.1 2. 8 52 Ratio 2 3/4 212 4/4 2/2 2/2 4/4 1 Noreading taken wherever appear. 1 Fractions indicate the ratio ofindividuals with demonstrable levels to the total number of individualsin the group.

TABLE IX.ERYTHROMYCIN SUSPENSION prednisollone are prepared from thefollowing types and [Single dose, 6.5 mg./lb.] amounts of ingredients:

\ [Pill starters prepared as in Example 1 (average diameter 0.0460047in.), 50,000,000] Blood level, mcgJml. 25 Age Weight Dose, M d 1 in s.mg. e ieina agent mixture Lb 1 hr. 3 hr. 5 hr. 8 hr. S OZ6a-methylprednisolone, micronized 3 6 118 Patient: Starch, bolted 6 2335 1 25 yr 32 200 .6 1 1 1 Sucrose, powdered a 3 1 16s 18 100 .s .15 .11 Tale 14 7 166 40 250 1 1 .1 1 v Ethylene oxide-polypropylene glycolconden- 46 300 12 11 55 1 sation product 1 4 179 31% 200 76 .5 .32 1932% 200 1 1 1 1 1 Pluronic F458, Wyandotte Chemical Company.

Average 131% .312 .zlg 1 Ram I I 35 The 6a-met-hylpredn1solone and anequal amount of the starch are uniformly mixed and the mixture ismicronized. fifi figigtitifitii fi fi ififii gf fi ifit gfifig 1thdemonstrable levels The mixture is then blended with the remainingstarch and other ingredients and bolted through number 11 Table Xprovides further blood level data comparing cloththe dosage forms of thepresent invention with other a. dosage forms now available to the art.The superiority of the enteric coated pilules illustrated by higher,more immediate and more consistent blood levels is clearly Coatingsolution Lbs. Oz. Grs.

Hydrolysed styrene-maleio anhydride copolymer apparent from anexamination of the data. Probably the M I 1 1 18 12 13 283 most strikingthing shown in the table is the fact that the i i fi g g 2$; (1mm 2 1$52 enteric coated pllules of the present 1nvent1on after two hours givethree times as high a blood level as the small, unenteric l r Thecopolymer is dissolved in the alcohol and the min- TABLE X.OOMPARISON OFERYIHROMYCIN BLOOD LEVELS AT VARIOUS INTERVALS AFTER ORAL ADMINISTRATIONOF ERYTHROSULFA PREPARATIONS [Dose: 400 mg. erythromycin (about 2.5mg./lb.). Time: V2 hour before breakfast] Blood level at intervals,hours Preparation Erythroruycin enteric pilules with triple sulfapilules Average range .458 .263 182 .114 .079 Ratio (0) 1 0. 81 0-. 4400-. 480 .072.236 .046-.144 8/9 8/9 8/9 9/9 9/9 Enteric coatederythromyein tablets laminated with Average range .3 49 .121 .063 .054triple Sums, Ratio 0 1 0-1. 34 0-. 654 .oso-. 22 0-. 0-. 1 8/10 9/1010/10 8/10 9/10 Erythromycin with triple sulfas flavored granules (notAverage rang .174 47 31 ent rie). Ratio (2) l 0-. 256 0-. 256 0-1.06 0-,230 0 1g6 5/10 7/10 7/10 7/10 4/10 Dn Average ran 086 045 058 031 R 0456 0-. 254 0-. 098 0-.1 0- 082 A 049 046 0g 0 Er throm cin with tri 1esulfas oral sus ension verage range 19 y y p p Ratio 0) 07- 280 0-..12 o.1o2 o- 1 0-. 08 10/10 6/10 8/10 5/10 3/10 X Fractions indicate theratio of individuals with demonstrable levels to the total number ofindividuals in the group.' Number in parentheses indicates number ofindividuals in the group who had no detectable erythromycm levels at an;interval.

EXAMPLE 6 eral oil is added. It is preferred to use 1 1b. 8 ozs. 297Steroid Pilules grs. of di-n-di butylphthalate as plastioizer in thecoating 50,000,000 enteric coated pilules containing 6a-methyl 75solution.

The ingredients are uniformly mixed using a No. 12 wire in the mixer.

Directions: The pill starters are sprayed in a revolving pill tub withdeionized water until uniformly moistened.

The medicinal agent mixture is dusted on the moistened starters. Thespraying and dusting are repeated until the average diameter of thepilules is from 0.048-0.049 in. The pilules are air dried and assayedtor steroid content.

The assayed pilules are coated with the coating solution using themagnesium stearate-talc mixture as dusting powder, until the averagediameter is from 0.0510.052 in. The coated pilules are assayed forsteroid content.

The coated pilules are encapsulated into two-piece hard gelatin capsuleseach containing 4 mgs. of 6u-methylprednisolone in the form of 140enteric-coated pilules.

The oral administration to humans of one to two capsules daily providesbeneficial results with lowered incidence of side eifects in rheumatoidarthritis. Advantageous, consistent blood levels of 17-OHcorticosteroids are obtained in the oral treatment of addisoniandisease.

EXAMPLE 7 Antimony Potassium Tartrate Pilules 10,000,000 pilules areprepared from the following types and amounts of materials:

[Pill starters prepared as in Example 1 (average diameter of 600 starteris 0.041 in.), 10,000,000]

In a revolving tub the starters are sprayed until uniformly wet with a1% aqueous solution of the polyoxyethylene sorbitan monolaurate.

A homogeneous mixture of the antimony potassium bitartrate, the canesugar, starch and talc is dusted on the wet starters. The spraying anddusting are repeated until the average diameter of 600 pilules is about0.048 in. The pilues are air dried and assayed for antimony potassiumbit-artrate content.

A-fter assay, the pilules are given several coats of hydrolysedstyrene-maleic anhydride copolymer in an anhydrous ethanol solutioncontaining mineral oil and di-nbuty-l phthalate, using the magnesiumstearate-talc mixture as a dusting powder. This procedure is continueduntil uniform spherical pilules with an average diameter of about 0.055in. are obtained. Beneficial results are obtained in the oral treatmentof dermal leishmaniasis at a daily dose of 3 to 4 capsules.

The pilules are encapsulated into two-piece hard gelatin capsules eachcontaining 22 mgs. of the medicinal agent in the form of 160 pilules.

EXAMPLE 8 Psychic Energizer Pilules Following the procedure of Example6, 1,000,000 enteric coated pilules are prepared from the followingtypes and amounts of materials.

12 Pill starters prepared as in Example 1 (average diameter 0.042 in.)1,000,000

Medicinal agent mixture:

Indole, 3-(2-aminobutyl)-, acetate gms 43.2 Starch, bolted gms 63.0Sucrose, powdered gms 31.5 Talc, bolted gms 147.6 Ethyleneoxide-polypropylene glycol condensation product gms 2.8

Coating solution:

Styrene-maleic acid copolymer gms 700 Ethanol anhydrous, denatured cc4670 Di-n-butylphthalate gms 84 White mineral oil, viscosity 180 gms 140Dusting powder:

Magnesium stearate, powdered gms Talc, bolted gms 420 Pluronic F-68,Wyandotte Chemical Company.

The average diameter of the enteric coated pilules is 0.052 in. pilulescontain 5 mgs. of the medicinal agent.

EXAMPLE 9 Androgenic Steroid Pilules Following the procedure of Example6, 10,000,000 enteric coated pilules are prepared from the followingtypes and amounts of ingredients:

[Pill starters prepared as in Example 1 (average diameter 0.041 in.),

Coating solution:

Polyvinyl acetate nhthal'lte Ethanol anhydrous, denaturedDi-n-butylphthalate White mineral oil, viscosity 180.--

Dusting powder:

Magnesium stearate, powdered 1, 280 Tale, bolted 512 The averagediameter of the enteric coated pilules is 0.055 in. pilules contain 10mg. of the therapeutically active ingredient.

The oral administration to male humans of one capsule daily providesbeneficial results in the treatment of androgen deficiencies.

This application is a continuation in part of co-pending applicationSerial Number 496,344, filed March 23, 1955, now abandoned.

What is claimed is:

1. An oral pharmaceutical preparation containing a plurality ofenteric-coated pilules each of which measures not more than about 0.1inch in diameter, is spherical, and has a uniform thickness of entericcoating and comprises (a) a medicinal agent and (b) a coating of asingle, non-toxic, acidic, enteric film-forming material surroundingsaid agent, the plurality providing a unit dose of the medicinal agent.

2. The preparation of claim 1 wherein the medicinal agent is atherapeutically active form of erythromycin.

3. The preparation of claim 1 wherein the medicinal agent is atherapeutically useful form of iron.

4. The preparation of claim 1 wherein the medicinal agent is atherapeutically active form of penicillin.

5. The preparation of claim 1 wherein the medicinal agent is atherapeutically active form of a salicylic acid salt.

6. The preparation of claim 1 wherein the medicinal agent is atherapeutically active form of a tetracycline.

7. The preparation of claim 1 wherein the medicinal agent is atherapeutically active form of a steroid hormone.

8. The preparation of claim 1 wherein the enteric filmforrning materialis cellulose acetate phthalate.

9. The preparation of claim 1 wherein the enteric film-forming materialis hydrolyzed styrene-maleic anhydride copolymer which is more thanfifty percent hydro- 1yzed.

10. The preparation of claim 1 wherein the enteric film-forming materialis styrene maleic acid copolymer.

11. The preparation of claim 1 wherein the pilules measure between about0.04 and 0.085 inch in diameter.

12. A process for preparing a plurality of spherical enteric-coatedpilules which comprises preparing uniform spherical pill starters,applying thereto a coating of a medicinal agent which is advantageouslyadministered orally in enteric-coated form and applying a coating of asingle, non-toxic, enteric film-forming material, each step being socarried out as to provide pilules measuring not more than about 0.1 inchin diameter.

13. The process of claim 12 wherein the pilules measure between about0.04 and about 0.085 inch in diameter.

14. An oral pharmaceutical capsule containing a plurality ofenteric-coated pilules each of which measures not more than about 0.1inch in diameter, is spherical, and has a uniform thickness of entericcoating and comprises (c z) 6a-methyleneprednisolone and (b) a coatingof hydrolyzed styrene-maleic anhydride copoly-mer as the single,non-toxic, acidic, enteric film-forming material surrounding said6a-methylprednisolone.

15. The capsule of claim 14 wherein the plurality of pilules containsabout 4 mgs. of 6a-methylprednisolone.

16. An oral pharmaceutical capsule containing a plurality ofenteric-coated pilules each of which measures not more than about 0.1inch in diameter, is spherical, and has a uniform thickness of entericcoating and comprises (a) a medicinal agent and (b) a coating of asingle, non-toxic, acidic, enteric film-forming material surroundingsaid agent, the plurality providing a unit dose of the medicinal agent.

17. An oral pharmaceutical packet containing a plurality ofenteric-coated pilules each of which measures not more than about 0.1inch in diameter, is spherical, and has a uniform thickness of entericcoating and comprises (a) a medicinal agent and (b) a coating of asingle,

' non-toxic, acidic, enteric film-foaming material surrounding saidagent, the plurality providing a unit dose of the medicinal agent.

References Cited in the file of this patent UNITED STATES PATENTS2,553,544 Bogin May 22, 1951 2,553,806 Bogin -a May 22, 1951 2,738,303Blythe Mar. 13, 1956 2,866,735 Himelick Dec. 30, 1958 FOREIGN PATENTS109,438 Australia Dec. 2 2, 1939 644,759 Germany May 112, 1939 428,941Great Britain May 22, 1935 715,305 Great Britain Sept. 8, 1954 OTHERREFERENCES New and Nonoflicial Remedies, 1955, I. B. Lippincott Co.,'pp. 188-189.

1. AN ORAL PHARMACEUTICAL PREPARATION CONSISTING A PLURALITY OFENTERIC-COATED PLULES EACH OF WHICH MEASURES NOT MORE THAN ABOUT 0.1INCH IN DIAMETER, IS SPHERICAL, AND HAS A UNIFORM THICKNESS OF ENTERICCOATING AND COMPRISES (A) A MEDICINAL AGENT AND (B) A COATING OF ASINGLE NON-TOXIC, ACIDIC, ENTERIC FILM-FORMING MATERIAL SURROUNDING SAIDAGENT, THE PLURALITY PROVIDING A UNIT DOSE OF THE MEDICINAL AGENT.